1. Field of the Invention
The present invention concerns a process for the catalytic asymmetric hydrogenation of β-ketoesters.
Useful pharmaceutical intermediates can be formed by the enantioselective hydrogenation of β-ketoesters. The hydrogenation is catalyzed by halogen-containing BINAP-Ru(II) complexes (Tetrahedron Letters, Vol. 32, No. 33, pp 4163–4166, 1991). The BINAP ligand (2,2′-bis (diphenylphosphino)-1, 1′-binaphthyl has the formula (1)

U.S. Pat. No. 6,162,951 discloses processes for the preparation of BINAP catalysts suitable for use in catalyzing asymmetric hydrogenation reactions. The use of Ru(OCOCH3)2[{S}-BINAP] in the enantioselective hydrogenation of ethyl 4-chloroacetoacetate is reported by Kitamura et al in Tetrahedron Letters, Vol. 29, No. 13, pp 1555–1556, 1988. Kitamura et al report that the reaction (scheme A) proceeds within 5 minutes giving the (R)-alcohol in 97% in enantiomeric excess.
2. Background Art
The same reaction was investigated by Pavlov et al in Russian Chemical Bulletin, Vol. 49, No. 4, April, 2000, pp 728–731. Pavlov et al studied the effects of the nature of the solvent, the reaction temperature, the pressure, addition of acids, and the reagent ratio on the yield and degree of an enantiomeric enrichment of the reaction products.
A substantial report in connection with reductions of 1,3-dicarbonyl systems with ruthenium-biarylbisphosphine catalysts has been prepared by Ager and Laneman, reported in Tetrahedron, Asymmetry, Vol. 8, No. 20, pp 3327–3355, 1997.
EP-A-0295109 teaches a process for preparing an optically active alcohol which comprises a symmetrically hydrogenating a β-keto acid derivative in the presence of a ruthenian-optically active phosphine complex as a catalyst. The resulting alcohol is said to have a high optical purity. Other examples of a symmetric hydrogenation reactions, and catalysts therefor, are disclosed in U.S. Pat. Nos. 5,198,561, 4,739,085, 4,962,242, 5,198,562, 4,691,037, 4,954,644 and 4,994,590.
Although the enantioselective hydrogenation of β-ketoesters has been extensively studied, there has to date been no satisfactory commercial development. In particular, these prior art studies have focussed largely on laboratory scale batchwise processing techniques where there is a requirement for high pressure and high temperature, something which is impractical on a commercial scale. In addition, the prior art processes require low substrate to catalyst ratios (typically in the region 2,000–10,000:1) to achieve a good enatioselectivity. BINAP or other bisaryl bisphosphine-based ligand catalyst are expensive and are often the largest cost in these processes. At low substrate to catalyst ratios, processes are often uneconomic. . . . One such process is described in WO-A-00/29370.